Abstract Body: Dysfunctional endothelial cells (ECs) contribute to the development of hypertension (HTN). Progranulin (PGRN) is a secreted protein that plays a major role in the inflammatory response. We recently demonstrated that HTN is associated with increased circulating PGRN, whereas the global lack of PGRN elicits vascular dysfunction and raises blood pressure (BP). However, the cellular origin of PGRN and the molecular mechanisms by which PGRN regulates vascular tone and BP are still to be elucidated. We hypothesized that ECs secrete PGRN, which regulates the vascular phenotype and BP in an autocrine manner. We used mice with tamoxifen-inducible, Cdh5-CreERT2-mediated deletion of PGRN in ECs (PGRN EC-/-) and their counterparts as controls (PGRN EC+/+). The effectiveness of endothelial PGRN depletion was validated using en face immunostaining in the aorta and qPCR in ECs from mesenteric arteries (MA). PGRN EC-/- mice exhibited a 2.5-fold reduction in circulating PGRN levels followed by EC dysfunction in MA characterized by reduced maximal response (Emax) and sensitivity (pD2) to acetylcholine [Emax (%): PGRN EC+/+: 99.3 ± 0.7 vs PGRN EC-/-: 95.9 ± 0.5* and pD2: PGRN EC+/+: 8.1 ± 0.2 vs PGRN EC-/-: 7.0 ± 0.3*, *P<0.05]. Supplementation with recombinant PGRN (20 μg/day) normalized endothelial function. Moreover, under baseline conditions, BP (analyzed by telemetry) was slightly higher in PGRN EC-/- mice [MAP (mmHg): PGRN+/+: 110.6 ± 1.6 vs PGRN-/-: 114.3 ± 1.2]. However, treatment with a subpressor dose of angiotensin II (120 ng/kg/day for 2 weeks) only increased BP in PGRN EC-/- mice. Mechanistically, we found that knockdown of PGRN (via siRNA) in cultured mesenteric ECs (MECs) suppressed PGRN secretion, AMPK phosphorylation, and nitric oxide (NO) formation. Conversely, MECs overexpressing PGRN (via lentivirus infection) led to exacerbated PGRN secretion followed by AMPK activation and NO formation, which were blunted by blocking AMPK or EphrinA2 (PGRN receptor) with dorsomorphin (10 μM) or ALWII4127 (5 μM), respectively. Finally, endothelial-specific AMPK-deficient mice exhibited increased BP and endothelial dysfunction in MA; such effects were not affected by PGRN treatment, suggesting that AMPK is a downstream target for PGRN. In summary, our data indicate that ECs are important sources of PGRN, which supports the maintenance of the EC phenotype and BP via EphrinA2, AMPK, and NO formation. This pathway occurs in an autocrine-dependent manner.